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INRAE

24, chemin de Borde Rouge -Auzeville - CS52627 31326 Castanet Tolosan cedex - France

Last update: May 2021

Menu Logo Principal logo Université Clermont Auvergne & associés

Human Nutrition Unit

Zone de texte éditable et éditée et rééditée

Dr Dragan MILENKOVIC

Researcher (PhD)

Impact of polyphenols on the developement of atherosclerosis and vascular function
Dragan MILENKOVIC

Mots Clés:

Polyphenols

Endothelium and vascular function

Nutri-epi,-genetic,-genomic

Integrative biology

Bioinformatics

Contact

Email : dragan.milenkovic[at]inrae.fr

Phone : +33(0)4 73 62 45 79

Citrus fruits, known for their CV health effects, are rich and exclusive sources of flavanones (hesperidin in oranges and naringin in grapefruit). Several cohort studies reported an inverse association between the level of intake of flavanones and incidence of CVD, but clinical data on the effect of flavanones are very rare [Chanet et al JAFC, 2012]. We conducted two randomized controlled clinical studies to characterize the role of flavanones in vascular protection of the citrus effect. The first study revealed the contribution of hesperidin in the effects of orange juice consuming (2.5 glasses / day) on the reduction in diastolic blood pressure (-3,2mmHg) and improvement in endothelial vasoreactivity (+ 48.7%) [Morand et al AJCN, 2011]. The second study demonstrated the role of naringin in the effects of regular consumption of grapefruit juice (2 drinks / day) on the reduction of arterial stiffness [Habauzit et al AJCN, 2015]. In mice fed an atherogenic diet, supplementation with nutritional doses of naringin reduced the progression of atherosclerotic lesions (-30%).
Identification des mechanismes d’action des polyphenols
The transcriptome analysis performed on leukocytes of volunteers consuming orange juice or the hesperidin showed that this flavanone plays important part in genomic effects of orange juice and modulate the gene expression to an anti-inflammatory and anti-atherogenic profile suggesting a lesser infiltration of immune cells into the vessel wall [Milenkovic et al, PLoS ONE, 2011]. In mice fed an atherogenic diet, supplementation with nutritional doses of naringin reduced the progression of atherosclerotic lesions (-30%) and modified the expression profile of genes involved in the processes that control the adhesion of monocytes to endothelial cells and their transendothelial migration, two key and early stages of development of atherosclerosis.

Publications  

  • Milenkovic D, Declerck K,  Guttman Y, Kerem Z, Claude S, Weseler A, Bast A, Schroeter H, Morand C, Wim Vanden Berghe. (-)-Epicatechins promote vascular health through epigenetic reprogramming of endothelial-immune cell signaling and reversing systemic low-grade inflammation. Biochemical Pharmacology (in press)
  • Krga I, Tamaian R, Mercier S, Boby C, Glibetic M, Morand C, and Milenkovic D. Anthocyanins and their gut metabolites attenuate monocyte adhesion and transendothelial migration through nutrigenomic mechanisms regulating endothelial cell permeability. Free radical biology & medicine 2018 Aug 20; 124:364-379
  • Yokoyama A, Dunaway K, Rutkowsky J, Rutledge J, and Milenkovic D. Chronic consumption of a Western diet modifies the DNA methylation profile in the frontal cortex of mice. Food Funct. 2018 Feb 21;9(2):1187-1198
  • Miquel S, Champ C, Day J, Aarts E, Bahr B, Bakker M, Bánáti D, CalabreseV, Cederholm T, Cryan J, Dye L, Farrimond J, Korosi L, Layé S, Maudsley S, Milenkovic D, Mohajeri M, Sijben J, Solomon A, Spencer J, Thuret S, Vanden Berghe W, Vauzour D, Vellas B, Wesnes K, Willatts P, Wittenberg R, Geurts L. Poor cognitive ageing: Vulnerabilities, mechanisms and the impact of nutritional interventions. Ageing Res Rev. 2017 Dec 15;42:40-55
  • Milenkovic D, Vanden Berghe W, Boby C, Leroux C, Declerck K, Szarc vel Szic K, Heyninck K, Laukens K, FuksF, Haegeman G, Haenen G, Bast A, Weseler A. Dietary flavanols modulate the transcription of genes involved in cardiovascular pathology with complex changes of their DNA methylation state. PloS ONE 2014
  • Afman L, Milenkovic D, Roche HM. Nutritional aspects of metabolic inflammation in relation to health-insights from transcriptomic biomarkers in PBMC of fatty acids and polyphenols. Mol Nutr Food Res. 2014 Jan 21. doi: 10.1002/mnfr.201300559
  • Claude S, Boby C, Rodriguez-Mateos A, Spencer JP, Gérard N, Morand C, Milenkovic D. Flavanol metabolites reduce monocyte adhesion to endothelial cells through modulation of expression of genes via p38-MAPK and p65-Nf-kB pathways. Mol Nutr Food Res. 2014 Jan 15. doi: 10.1002/mnfr.201300658
  • Milenkovic D, Jude B, Morand C. miRNA as post-translational targets of polyphenols. Free Radical Biology and Medicine 2013 Sep;64:40-51
  • Chanet A, Milenkovic D, Claude S, Maier JAM, Khan M, Shinkaruk S, Bérard AM, Bennetau-Pelissero C, Mazur A, Morand C. Flavanone metabolites decrease monocyte adhesion to endothelial cells by modulating expression of related genes. British Journal of Nutrition 2013 Jan 21:1-12
  • Chanet A, Wizinska P, Polakof S, Mazur A, Bennetau-Pelissero C, Morand C, Bérard A and Milenkovic D. Naringin at a nutritional dose modulates expression of genes related to lipid metabolism and inflammation in liver of mice fed a high-fat diet. Nurition and Aging 2012 (1): 113-123
  • Coban D, Milenkovic D, Chanet A, Khallou-Laschet J, Sabbe L, Palagani A, Vanden Berghe W, Mazur A, Morand C. Dietary curcumin inhibits atherosclerosis by affecting the expression of genes involved in leukocyte adhesion and transendothelial migration. Mol Nutr Food Res. 2012 Aug;56 (8):1270-81
  • Chanet A, Milenkovic D, Manach C, Mazur A, Morand C. Citrus flavanones: what is their role in cardiovascular protection? J Agric Food Chem. 2012 Sep 12;60(36):8809-22

Grant

- « L'impact des métabolites circulants des flavanols sur l'expression des miRNA et leurs gènes cibles au niveau des cellules endothéliales». Prix de Recherche attribué par la Société Française de la Nutrition (SFN); 20 k€, responsable du projet
- « Micronutriments et modulation du profil d’expression des miARN des microparticules endothéliales en situation de stress inflammatoire ». ANSSD-INRA (2013-2014) ; 12 k€, responsable du projet
- « Identification of cellular and molecular targets of plant bioactives on human blood cells ». Project d’échanges scientifiques et technologiques d'excellence dans le cadre de Partenariat Hubert Curien - Pavle Savic avec une laboratoire de Belgrade, Serbie (2011-2013); 6 k€, responsable du projet.
- Projet de recherche Citrus2 “Effects of grapefruit juice consumption on vascular function - A human cross-over study on the specific contribution of citrus flavanones”, Grant of Florida Department of Citrus, Florida States, US (2010-2013) ; 527 k€, coordinateur : C Morand
- « Determination of cellular and molecular mechanisms of orange juice polyphenols in human monocytes », Grant of Florida Department of Citrus, Florida States, US (2011-2012) ; 29 k€, responsable du projet
- Projet Européen FLAVIOLA (FP7 - KBBE) - Membre du Comité de Pilotage “Targeted delivery of dietary flavanols for optimal human cell function: Effects on cardiovascular health”, Coord. Univ Düsseldorf (2009-2013) ; 300 k€, task leader